OP0141 LONG TERM SAFETY AND EFFICACY OF CAR-T CELL TREATMENT IN REFRACTORY SYSTEMIC LUPUS ERYTHEMATOSUS - DATA FROM THE FIRST SEVEN PATIENTS
Authors: J. Taubmann, F. Müller, S. Boeltz, S. Völkl, M. Aigner, A. Kleyer, I. Minnopoulou, F. Locatelli, M. A. D’agostino, R. Gary, S. Krestchmann, S. Kharboutli, D. Mougiakakos, G. Krönke, M. Andreas, G. Schett
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Despite better treatment modalities some patients with systemic lupus erythematosus (SLE) suffer from severe and treatment-resistant disease. This situation puts patients at high risk for organ failure or even death. Furthermore, many patients with SLE have to take long-term, sometimes even life-long immune suppressive medication to control the disease without being able to enjoy drug-free remission. Recently, we reported that deep B cell depletion using a single infusion with autologous CD19 chimeric antigen receptor (CAR) T cells induced drug-free clinical remission in severe SLE patients with refractory disease [1,2]. This abstract presents the long-term clinical efficacy and safety data of the first seven SLE patients receiving autologous CD19-directed CAR-T cell therapy. <h3>Objectives</h3> To test whether administration of autologous CD19 chimeric antigen receptor (CAR) T cells is tolerable and effective in patients with severe refractory SLE. <h3>Methods</h3> Compassionate use program for patients with severe active SLE showing organ involvement and resistance to multiple immune suppressive treatments. Patients received autologous 1x10<sup>6</sup> CD19-CAR-T cells/kg body weight by single infusion after standard conditioning therapy (cyclophosphamide/fludarabine). The investigational medicinal product MB-CART19.1 was produced as described before [1,2]. All SLE treatments were stopped before CAR-T cell administration. Patients were followed up as in-patients for the first 10 days after CAR T cell administration, then weekly until the end of the first month, then monthly for three months and every three months thereafter. Tolerability was assessed by monitoring for Cytokine-release syndrome (CRS) and Immune-related effector Cell Neurotoxicity Syndrome (ICANS). Preliminary efficacy was assessed by reaching a Lupus Low Disease Activity State (LLDAS) and DORIS remission. <h3>Results</h3> As per January 2023, seven SLE patients (6 female, 1 male, aged range 19-39) had been treated with CD19 CAR-T cells with a median follow up of 13 months (4 months-22months). Patients had active disease with a median SLEDAI of 10 (range: 8-16), with a median of 4 organs involved (range: 8-16) and a median number of 7 failed treatments (range: 4-15). All patients had active kidney disease. In addition, involvement of the heart, lungs, pleura, joints, skin, muscles and bone marrow were documented. Conditioning was done at the described [1,2] dose with the exception of patients 7, who received only 50% of the dose. All patients received a single infusion of 1x10<sup>6</sup> autologous CD19-CAR-T cells/kg body weight. No ICANS was observed and CRS if observed were mild (grade I). In vivo, CAR-T cells rapidly expanded peaking at day 9 with a median of 26% of circulating T cells being CAR T cells (range: 11-59%). Expansion of CAR-T cells coincidence with the complete depletion of circulating B cells. B cell aplasia lasted for a median of 120 days (range 58-205). All patients experienced drug-free remission as assessed by DORIS remission criteria and met lupus low activity state (LLDAS) usually within the first three months after CAR T cell therapy. Furthermore, seroconversion with loss of dsDNA antibodies and other autoantibodies was observed. To date, no SLE flare occurred despite complete cessation of treatment. <h3>Conclusion</h3> Taken together, these data suggest that CD19 CAR T-cell therapy can abrogate disease and delete autoimmunity in patients with severe SLE. After CD19 CAR T-cell therapy SLE patients remain in drug free-remission of SLE even if B cells recur. This remission can be long-lasting as the longest disease -free observation period is now 22 months. <h3>References</h3> [1] Mougiakakos D et al., CD19-Targeted CAR T Cells in Refractory Systemic Lupus Erythematosus. N Engl J Med 2021;385:567-569. [2] Mackensen A. et al., Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus; Nat Med 2022 Oct; 28(10):2124-2132. <h3>Acknowledgements</h3> The study was supported by the Deutsche Forschungsgemeinschaft (FOR2886, CRC1181 and TRR221), the Bundesministerium für Bildung und Forschung (BMBF; MASCARA), the European Union (ERC Synergy grant 4D Nanoscope, ERC Consolidator grant INSPIRE) and the IMI-funded project RTCure. We thank S. Miltenyi for fruitful discussions, D. Werner and J. Hofer for assistance. <h3>Disclosure of Interests</h3> None Declared.